Parkinson's disease (PD) is characterized by the degeneration of dopamine producing cells in the substantia nigra. Although the neurochemical lesion is mainly localized to the nigrostriatal dopamine system, the effects of dopamine loss are widespread and affect non-dopaminoceptive neurons in brain regions constituting crucial elements of motor control and other pathways. These systems, which are still incompletely delineated, play a critical role in mediating the prominent motor and cognitive impairments of PD. In the past funding period, we utilized positron emission tomography (PET) and brain network analysis to identify specific functional alterations in these pathways in PD. Specifically, we utilized an integrated approach involving brain imaging, motor control physiology, and stereotaxic neurosurgery to explore mechanisms of clinical disability in this disease. Using network analysis, we found evidence of abnormal brain-behavior relationships in untreated PD patients at early stages of disease. importantly, we also found that both medical therapy with levodopa as well as surgical therapy with pallidal deep brain stimulation (DBS) improved the manifestations of parkinsonism and corrected PD-related brain network abnormalities. Moreover, we found evidence that DBS procedures may also have a positive effect on motor learning as well as execution. In this continuation application, we seek to expand upon these results to study therapeutic mechanisms for manifestations of PD for which conventional treatments are typically ineffective. We will use our brain imaging methodology in conjunction with DBS to identify the effects of successful therapy on the modulation of PD networks associated with cognition and motor behavior. These studies will utilize on-line psychophysical performance indices of motor performance and learning in conjunction with PET measurements of local cerebral function to evaluate the modulation of specific brain networks in the course of DBS. This integrated approach will allow us to assess changes in brain-behavior relationships brought about by successful interventions utilizing this new therapeutic strategy. In other experiments, we propose to utilize PET imaging with DBS to assess specific pathways associated with the mediation of parkinsonian tremor and levodopa induced dyskinesias. In the proposed studies, we will examine the effects of selected forms of DBS on the modulation of specific brain networks thought to mediate these manifestations. The studies will also utilize state-of-the-art on-line biodynamic measurements in conjunction with dopaminergic therapeutic interventions. Utilizing an integrated approach with network analysis, we will seek to delineate pathways associated with these troubling manifestations of parkinsonism. The proposed studies will allow us to utilize functional imaging, physiologic, and pharmacologic techniques to explore the basis for fixture therapies for parkinsonian manifestations that are currently refractory to existing forms of treatment.